Download Inspiratory Fraction Correlates With Exercise

Inspiratory Fraction Correlates With Exercise Capacity
in Patients With Stable Moderate to Severe COPD
Yan Zhang MD, Xing-Guo Sun MD, Wen-Lan Yang MD,
Xiao-Yue Tan MD, and Jin-Ming Liu MD
BACKGROUND: Exercise intolerance is the hallmark of COPD. Static lung hyperinflation and
increased dynamic hyperinflation during exercise are associated with reduced functional capacity
in COPD patients. Inspiratory capacity correction for the total lung capacity, defined as inspiratory
fraction (IF), may be functionally more representative than other traditional indices in these patients. OBJECTIVE: To investigate the association between IF and exercise capacity in patients
with stable, moderate to severe COPD. METHODS: Fifty COPD subjects and 34 healthy volunteers
constituted the study cohort. Pulmonary function and cardiopulmonary exercise testing were performed, and ventilation and gas exchange parameters were measured. RESULTS: IF was significantly correlated with percent-of-predicted peak oxygen consumption (V̇O2) in the subjects with
COPD (r ⴝ 0.52, P < .001). IF was an independent predictor of reduced exercise capacity in the
COPD subjects, and was more sensitive and specific than percent-of-predicted FEV1. Statistical
analysis generated the equation: percent-of-predicted peak V̇O2 ⴝ 65.9 IF ⴙ 0.45 percent-of-predicted FEV1 ⴙ 35.8 (RC2 ⴝ 0.39, P < .001). The subjects with IF < 0.23 had more severe lung
hyperinflation and less exercise capacity than the subjects with IF > 0.23. At peak exercise, the
breathing frequencies of the 2 groups were similar, whereas the low-IF subjects had reduced peak
minute ventilation and peak tidal volume, relative to the high-IF subjects. CONCLUSIONS: Compared to FEV1, IF is a robust factor to reflect lung hyperinflation and to estimate the exercise
capacity of subjects with stable moderate to severe COPD. Key words: COPD; inspiratory fraction;
lung hyperinflation; cardiopulmonary exercise test; inspiratory capacity. [Respir Care 2013;58(11):
1923–1930. © 2013 Daedalus Enterprises]
Introduction
COPD is recognized as the fourth leading cause of death
worldwide and a major chronic respiratory disorder due to
different diseases causing medical disability. COPD is characterized by air-flow limitation that is poorly reversible,
The authors are affiliated with the Department of Respiratory Medicine,
Shanghai Pulmonary Hospital, Tongji University, Shanghai, China, with
the exception of Dr Sun, who is affiliated with the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
The authors have disclosed no conflicts of interest.
Correspondence: Jin-Ming Liu MD, Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University, 507 Zhengmin
Road, Shanghai 200433, China. E-mail: [email protected].
DOI: 10.4187/respcare.01927
RESPIRATORY CARE • NOVEMBER 2013 VOL 58 NO 11
progressive, and associated with an abnormal inflammatory response of the lung to noxious particles, such as the
materials released from smoking.1 The hallmark of COPD
is exercise intolerance and exertional dyspnea, which are
due to complex interactions between impaired ventilatory,
cardiovascular, and peripheral muscle responses. The major abnormality of respiratory muscle dysfunction in COPD
patients is the mechanical disadvantage caused by lung
hyperinflation. Static lung hyperinflation at rest and increased dynamic hyperinflation during exercise are associated with reduced functional capacity in these patients.2
Over the decades, it has been widely accepted that traditional measures of air-flow obstruction, such as FEV1 and
FEV1/FVC, are repeatable and reliable for the diagnosis
and prognosis of COPD. However, increasing evidence
demonstrates that FEV1/FVC does not reflect the level of
lung hyperinflation and is poorly correlated with exercise
capacity and exertional dyspnea in COPD patients.1,2
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INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
Recently, inspiratory capacity (IC) at rest and during
exercise has been shown to be superior to traditional predictive parameters like FEV1.3 IC reflects the level of lung
hyperinflation and is associated with the functional reserve
in patients with COPD. Moreover, the ratio of IC to total
lung capacity (IC/TLC, called the inspiratory fraction or
IF) provides a better characterization of the volume fraction available for inspiration than does IC alone,4 and IF
predicts exercise capacity in patients with moderate to
severe COPD. In the current study we compared the functional parameters of ventilation, gas exchange, and exercise capacity in patients with stable moderate to severe
COPD. We also analyzed the breathing patterns and exertional dyspnea of these patients with standard pulmonary function tests (PFTs) and cardiopulmonary exercise
testing (CPET). Our objective was to investigate the relationship between IC, IF, and other parameters and the
exercise capacity of patients with COPD, to determine if
IF is a robust predictor of exercise capacity in COPD
patients.
IN
PATIENTS WITH COPD
QUICK LOOK
Current knowledge
Exercise intolerance is common and decreases quality
of life in patients with COPD. Static lung hyperinflation and increased dynamic hyperinflation during exercise reduce functional capacity in COPD patients.
What this paper contributes to our knowledge
Inspiratory fraction (inspiratory capacity/total lung capacity) independently predicted reduced exercise capacity in patients with moderate to severe COPD. An
inspiratory fraction of ⬎ 0.23 was associated with worse
lung hyperinflation and reduced exercise capacity.
The protocol was approved by our hospital’s ethics review board. All subjects signed written informed consent
before enrollment. Patients diagnosed as having COPD
stage II (n ⫽ 16) and stage III (n ⫽ 34) at the Department
of Respiratory Medicine, Shanghai Pulmonary Hospital,
between July 2010 and June 2011, were recruited for this
study. Diagnosis and classification were based on the Global
Initiative for Chronic Obstructive Lung Disease 2010 guidelines.5 All subjects accepted regular treatment and had
stable COPD for at least 4 weeks prior to enrollment. More
than 400 patients were screened for this study, by analyzing patient history, PFTs, heart color Doppler ultrasound,
and computed tomograms. Patients with other diseases
that cause breathing discomfort and impaired exercise capacity, such as asthma, pulmonary arterial hypertension,
interstitial lung disease, other concomitant lung disease,
heart failure, metabolic disorders, and/or skeletal muscle
diseases, were excluded. As a control group, 34 healthy
volunteers of similar ages participated in the study. Professional athletes and laborers were excluded.
Age, sex, body weight, and height of all subjects were
recorded, and body mass index was calculated. PFTs were
performed (MasterScreen-PFT, Erich Jaeger, Friedberg,
Germany) before and after bronchodilator. Every subject
completed at least 3 acceptable tests, with an interval of
1 min. The variability between the 3 tests was ⬍ 5%, and
the results of the best trial were recorded. Collected parameters included FVC, FEV1, FEV1/FVC, maximal voluntary ventilation (MVV), IC, TLC, residual volume (RV),
RV/TLC, and diffusing capacity of the lung for carbon
monoxide (DLCO) (corrected for hemoglobin). PFT parameters are expressed as percent-of-predicted values, which
were calculated using the equations designed for Chinese
adults in 1988.6
Symptom-limited CPET was conducted on a cycle ergometer, using a cardiopulmonary exercise testing system
(MasterScreen-CPX, Erich Jaeger, Friedberg, Germany)
and a gas analysis system (SBx/CPX, Erich Jaeger, Friedberg, Germany).7 The increasing work rate was individually selected from 10 W/min to 25 W/min, to provide a
total exercise duration of 8 –12 min. During the whole
procedure we monitored a 12-lead online electrocardiogram, blood pressure, SpO2, and gas exchange. Gas exchange data were recorded, breath-by-breath, and averaged over 10-second intervals, followed by further
analysis.8-10 The tests were terminated if the subject had
any of the following conditions: ischemic electrocardiogram changes (ST depression of 2 mm with chest pain, or
ST depression of 3 mm without chest pain), frequent premature ventricular contractions, conduction disorders,
systolic pressure ⬎ 250 mm Hg, diastolic pressure
⬎ 120 mm Hg, a fall in systolic pressure ⬎ 20 mm Hg
from the highest value obtained during the test, and/or an
SpO2 ⬍ 80%. Typical symptoms for stopping were leg
fatigue, weakness, or shortness of breath. The CPET variables were peak load, peak oxygen uptake (V̇O2), peak O2
pulse, minute ventilation (V̇E), breathing frequency, tidal
volume (VT), heart rate, and heart rate reserve (predicted
heart rate – peak heart rate) (predicted heart rate ⫽ 220 –
age). Anaerobic threshold was determined by the V-slope
method.11 The intensity of dyspnea at peak exercise was
described as peak V̇E/MVV. CPET parameters were expressed as percent-of-predicted values, which were calculated with the equations from the American Thoracic Society/American College of Chest Physicians in 2003.12
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RESPIRATORY CARE • NOVEMBER 2013 VOL 58 NO 11
Methods
INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
Table 1.
IN
PATIENTS WITH COPD
Demographics and Pulmonary Function and Cardiopulmonary Exercise Testing Results From COPD Subjects Versus Normal Subjects
Male/female
Age, y
Body mass index, kg/m2
FVC, % predicted
FEV1, % predicted
FEV1/FVC, %
TLC, % predicted
Inspiratory capacity, % predicted
Inspiratory fraction
RV, % predicted
RV/TLC, %
DLCO, % predicted
PaO2, mm Hg
PaCO2, mm Hg
Peak work, W
Peak work, % predicted
Peak V̇O2, mL/min
Peak V̇O2, % predicted
Peak heart rate, beats/min
Peak V̇E, L/min
Peak breathing frequency, breaths/min
Peak VT, L
Peak O2 pulse, mL/beat
Peak O2 pulse, % predicted
Peak V̇E/maximum voluntary ventilation
Anaerobic threshold, mL/min
V̇E/V̇CO2 at anaerobic threshold
COPD Subjects
n ⫽ 50
Normal Subjects
n ⫽ 34
P
45/5
63 ⫾ 6
23 ⫾ 3
26/8
60 ⫾ 7
24 ⫾ 3
.09
.08
.12
84.82 ⫾ 14.5
46.48 ⫾ 11.88
44.05 ⫾ 7.42
124.5 ⫾ 23.31
65.2 ⫾ 20.73
0.25 ⫾ 0.07
189.49 ⫾ 42.61
58.89 ⫾ 7.7
83.89 ⫾ 25.57
79 ⫾ 10
38 ⫾ 4
102.44 ⫾ 11.49
98.30 ⫾ 11.51
77.55 ⫾ 4.51
103.27 ⫾ 7.82
91.34 ⫾ 21.0
0.43 ⫾ 0.10
109.82 ⫾ 10.18
38.87 ⫾ 5.07
108.0 ⫾ 25.0
90 ⫾ 2
36 ⫾ 2
⬍ .001
⬍ .001
⬍ .001
.002
.001
⬍ .001
⬍ .001
⬍ .001
.004
⬍ .001
.33
93 ⫾ 29
82.76 ⫾ 23.57
1,279.72 ⫾ 301.86
73.41 ⫾ 13.75
133 ⫾ 19
41.88 ⫾ 10.1
32 ⫾ 6
1.33 ⫾ 0.36
9.62 ⫾ 1.68
91.31 ⫾ 13.53
1.04 ⫾ 0.19
956.48 ⫾ 215.69
35.23 ⫾ 4.94
137 ⫾ 33
115.68 ⫾ 20.89
1,643.85 ⫾ 331.52
91.71 ⫾ 12.13
151 ⫾ 16
60.74 ⫾ 15.27
34 ⫾ 6
1.83 ⫾ 0.47
10.98 ⫾ 2.24
100.56 ⫾ 16.23
0.71 ⫾ 0.21
1,136.91 ⫾ 242.63
30.69 ⫾ 3.67
⬍ .001
⬍ .001
⬍ .001
⬍ .001
⬍ .001
⬍ .001
.33
⬍ .001
.002
.006
⬍ .001
⬍ .001
⬍ .001
Values are mean ⫾ SD.
TLC ⫽ total lung capacity
RV ⫽ residual volume
DLCO ⫽ diffusing capacity of the lung for carbon monoxide
V̇E ⫽ minute volume
V̇O2 ⫽ O2 consumption
VT ⫽ tidal volume
V̇CO2 ⫽ CO2 clearance
ity ⫹ specificity ⫺1).14 A P value ⬍ .05 was considered
statistically significant.
All statistical analyses were performed with statistics
software (SPSS 19.0, SPSS, Chicago, Illinois). Data are
expressed as mean ⫾ SD. P values between groups were
calculated using the chi-square test or the unpaired Student
t test. Pearson correlation coefficients were calculated to
assess the correlations between variables. Backward, stepwise, multiple linear regression was performed to determine the independent predictors. Receiver operating characteristic (ROC) curves were created for selected variables,
to evaluate the sensitivity and specificity of PFT parameters as predictors for percent-of-predicted peak V̇O2.13 The
Youden index was calculated to find the cutoffs for variables. The Youden index is defined as the maximum vertical distance between the ROC curve and the diagonal or
chance line, and is calculated as maximum (sensitiv-
Fifty subjects with stable, moderate or severe COPD
and 35 healthy volunteers participated in this study. Table 1 shows the demographics of all the subjects and the
results of PFTs and CPET. There were no significant differences between the 2 groups in sex, age, or body mass
index. Percent-of-predicted FEV1 (FEV1%) in the COPD
subjects demonstrated moderate to very severe obstruction
(FEV1% range 32–75%). Nearly all the COPD subjects
RESPIRATORY CARE • NOVEMBER 2013 VOL 58 NO 11
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Results
PFT and CPET Values
INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
IN
PATIENTS WITH COPD
Fig. 1. Inspiratory fraction versus percent-of-predicted peak oxygen uptake (V̇O2) in subjects with stable, moderate to severe COPD.
had lung volume measurements suggestive of air trapping
(percent-of-predicted RV range 129 –296%, n ⫽ 48), and
DLCO was decreased in nearly half (percent-of-predicted
DLCO 37% to 79%, n ⫽ 24).
In the CPET we observed significant reductions in peak
work, percent-of-predicted peak work, peak V̇O2, percentof-predicted peak V̇O2, and anaerobic threshold in the COPD
subjects, compared to the normal subjects (P ⬍ .001).
Twenty-six percent of the COPD subjects displayed a severe reduction in percent-of-predicted peak V̇O2 (⬍ 65%,
n ⫽ 13).10 The ratio of V̇E to CO2 production (V̇E/V̇CO2) at
anaerobic threshold in the COPD subjects was significantly higher than in the normal subjects. At peak exercise, gas exchange analysis showed that there was no significant difference for peak breathing frequency between
the 2 groups (P ⫽ .33). However, peak V̇E (44.95 ⫾ 12.94 L/
min) and peak VT (1.43 ⫾ 0.39 L) in the COPD subjects
were dramatically decreased, compared to the control group
(60.74 ⫾ 15.27 L/min and 1.83 ⫾ 0.47 L, respectively,
P ⬍ .001). The peak V̇E/MVV of 98% of the COPD subjects was ⬎ 0.7, suggesting a severely reduced breathing
reserve in the COPD subjects at peak exercise.12 Moreover, the peak V̇E/MVV of the COPD subjects was worse
than the control group (1.04 ⫾ 0.19 and 0.71 ⫾ 0.21,
respectively, P ⬍ .001).
Fig. 2. Receiver operating characteristic curves for inspiratory fraction, percent-of-predicted inspiratory capacity, and percent-ofpredicted FEV1 for predicting the change in percent-of-predicted
peak oxygen uptake (⬍ 65%). The areas under the curve are 0.933
(95% CI 0.862–1.000, P ⬍ .001), 0.849 (95% CI 0.737– 0.962,
P ⬍ .001), and 0.853 (95% CI 0.751– 0.955, P ⬍ .001), and the
cutoffs are 0.23, 43%, and 60%, respectively.
(r ⫽ ⫺0.25, P ⫽ .08), IF (r ⫽ 0.52, P ⬍ .001, Fig. 1), and
FEV1% (r ⫽ 0.54, P ⬍ .001). Backward stepwise multiple
linear regression analysis generated the equation:
Percent-of-predicted peak V̇O2
⫽ 65.9 IF ⫹ 0.45 FEV1% ⫹ 35.8
RC2 (the adjusted determination coefficient) ⫽ 0.39 and
P ⬍ .001. The results reveal that IF and FEV1% are independent predictors of exercise capacity in COPD subjects.
IF as a Predictor of Exercise Capacity in COPD
Subjects
The percent-of-predicted peak V̇O2 was significantly related to some PFT parameters, including percent-of-predicted IC (IC%) (r ⫽ 0.43, P ⫽ .002), percent-of-predicted
RV (r ⫽ ⫺0.52, P ⬍ .001), percent-of-predicted TLC
Based on the above findings, we then compared the
sensitivity and specificity of IF, IC%, and FEV1% as predictors of percent-of-predicted peak V̇O2 in the COPD subjects, by analyzing the ROC curves. The areas under the
curve were 0.933 (95% CI 0.862–1.00, P ⬍ .001), 0.849
(95% CI 0.737– 0.962, P ⬍ .001), and 0.853 (95% CI
0.751– 0.955, P ⬍ .001), respectively (Fig. 2). When we
chose 0.23 as the cutoff for IF, the sensitivity, specificity,
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RESPIRATORY CARE • NOVEMBER 2013 VOL 58 NO 11
Association Between PFT Parameters and Percent-ofPredicted Peak V̇O2 in the COPD Subjects
INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
Table 2.
IN
PATIENTS WITH COPD
Demographics and Pulmonary Function and Cardiopulmonary Exercise Testing Results From Subjects With Inspiratory Fraction Less
Than Versus More Than 0.23 Inspiratory Fraction
Age, y
Body mass index, kg/m2
FVC, % predicted
FEV1, % predicted
FEV1/FVC, %
TLC, % predicted
Inspiratory capacity, % predicted
Inspiratory fraction
RV, % predicted
RV/TLC, %
DLCO, % predicted
PaO2, mm Hg
PaCO2, mm Hg
Peak work, W
Peak work, % predicted
Peak V̇O2, mL/min
Peak V̇O2, % predicted
Peak heart rate, beats/min
Peak heart rate, % predicted
Heart rate reserve, beats/min
Peak V̇E, L/min
Peak breathing frequency, breaths/min
Peak VT, L
Peak O2 pulse, mL/beats
Peak O2 pulse, % predicted
Peak V̇E/maximum voluntary ventilation
Anaerobic threshold, L/min
V̇E/V̇CO2 at anaerobic threshold
Stopping reason, no.
Breathing discomfort
Leg fatigue
Breathing discomfort and leg fatigue
⬍ 0.23
n ⫽ 18
ⱖ 0.23
n ⫽ 32
P
64 ⫾ 8
22 ⫾ 3
62 ⫾ 7
23 ⫾ 3
.48
.18
79.03 ⫾ 11.22
39.59 ⫾ 5.81
40.43 ⫾ 5.93
138.04 ⫾ 29.66
52.97 ⫾ 11.25
0.18 ⫾ 0.04
222.58 ⫾ 35.77
63.83 ⫾ 5.95
64.98 ⫾ 25.21
76 ⫾ 10
39 ⫾ 4
88.07 ⫾ 15.26
50.36 ⫾ 12.7
46.09 ⫾ 7.47
116.89 ⫾ 14.48
72.09 ⫾ 21.77
0.29 ⫾ 0.06
170.87 ⫾ 34.27
56.25 ⫾ 7.27
94.86 ⫾ 22.68
81 ⫾ 9
36 ⫾ 4
.03
.001
.008
.001
.001
⬍ .001
⬍ .001
⬍ .001
⬍ .001
.21
.04
71 ⫾ 23
70.86 ⫾ 23.06
1,061.44 ⫾ 210.36
62.57 ⫾ 11.97
122 ⫾ 17
72.43 ⫾ 9.12
34 ⫾ 15
36.47 ⫾ 4.87
33 ⫾ 6
1.13 ⫾ 0.25
8.72 ⫾ 1.46
86.06 ⫾ 13.47
1.06 ⫾ 0.16
856.9 ⫾ 210.95
37.93 ⫾ 4.69
103 ⫾ 29
89.46 ⫾ 21.4
1,402.49 ⫾ 276.65
79.5 ⫾ 10.67
139 ⫾ 18
81.8 ⫾ 9.72
19 ⫾ 16
44.93 ⫾ 11.03
32 ⫾ 6
1.45 ⫾ 0.37
10.12 ⫾ 1.6
94.27 ⫾ 12.84
1.04 ⫾ 0.21
989.68 ⫾ 210.23
34.33 ⫾ 4.76
.001
.006
⬍ .001
⬍ .001
.002
.002
.002
.001
.29
.001
.003
.04
.72
.09
.045
.03
13
3
2
11
15
6
Values are mean ⫾ SD.
TLC ⫽ total lung capacity
RV ⫽ residual volume
DLCO ⫽ diffusing capacity of the lung for carbon monoxide
V̇O2 ⫽ O2 consumption
V̇E ⫽ minute volume
VT ⫽ tidal volume
V̇CO2 ⫽ CO2 clearance
Comparison of PFT and CPET Parameters in COPD
Subjects With High or Low IF
and Youden index of IF as an independent factor were
0.923, 0.837, and 0.76, respectively. Similarly, the cutoff
for FEV1% was 43%, and the sensitivity, specificity, and
Youden index were 0.722, 0.929 and 0.651, respectively.
The cutoff of IC% was 63% and the sensitivity, specificity, and Youden index were 0.722, 0.929, and 0.651, respectively. The data reveal that IF is the best factor among
PFT parameters for predicting exercise capacity in COPD
subjects.
According to the calculated Youden index, we chose
0.23 as the cutoff for IF, and divided the COPD subjects
into 2 groups: IF ⬍ 0.23 (n ⫽ 18), and IF ⱖ 0.23 (n ⫽ 32).
Table 2 shows the respective PFT parameters of the 2
groups: FEV1% was 39.59 ⫾ 5.81% and 50.36 ⫾ 12.7%,
percent-of-predicted TLC was 138.04 ⫾ 29.66% and
RESPIRATORY CARE • NOVEMBER 2013 VOL 58 NO 11
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INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
IN
PATIENTS WITH COPD
Fig. 3. Tidal volume (VT) during cardiopulmonary exercise testing
in subjects with COPD and an inspiratory fraction ⬍ 0.23 or ⱖ 0.23.
The duration of rest was an average of 120 s before ending the
period. The duration of warm-up was an average of 30 s before
ending the period. The anaerobic threshold was determined by the
V-slope method. The duration of peak exercise was an average of
30 s before the peak load. The whisker bars indicate the 95% CIs.
* P ⬍ .05.
116.89 ⫾ 14.48%, percent-of-predicted RV was
222.58 ⫾ 35.77% and 170.87 ⫾ 34.27%, and IC% was
52.97 ⫾ 11.25% and 72.09 ⫾ 21.77%. These data suggest
that the IF ⬍ 0.23 group had worse air-flow obstruction
and higher lung hyperinflation than the IF ⱖ 0.23 group.
The CPET results reveal that the peak percent-of-predicted
V̇O2 of 6 subjects in the IF ⬍ 0.23 group was ⬎ 65%, and that
of the rest was ⬍ 65%. The percent-of-predicted peak V̇O2 of
one subject in the IF ⱖ 0.23 group was ⬍ 65%, and that of
the rest was ⬎ 65%. Breathing pattern analysis at peak exercise showed that the peak breathing frequency was not
significantly different between the 2 COPD groups (P ⫽ .29).
However, the peak V̇E (36.47 ⫾ 4.87 L/min) of the IF ⬍ 0.23
group was significantly lower than that of the IF ⱖ 0.23
group (44.93 ⫾ 11.03 L/min) (P ⫽ .001), and VT at anaerobic threshold and peak exercise (1.05 ⫾ 0.14 L and
1.13 ⫾ 0.25 L) of the IF ⬍ 0.23 group were significantly
lower than those (1.23 ⫾ 0.28 L and 1.45 ⫾ 0.37 L) of the
IF ⱖ 0.23 group (P ⫽ .01 and 0.001, Fig. 3.). The patterns of
the change of VT and breathing frequency in CPET (Fig. 4)
revealed that the VT of COPD subjects with IF ⬍ 0.23 did not
increase substantially when the exercise load was increasing,
and that VT at peak exercise almost reached the IC at rest. In
contrast, the VT of COPD subjects with IF ⬎ 0.23 increased
when the exercise load was increasing, and the VT at peak
1928
Fig. 4. Representative tidal volume (VT) and breathing frequency (f)
patterns of subjects with COPD and normal subjects during cardiopulmonary exercise testing. A: COPD subject with inspiratory
fraction (IF) 0.15, inspiratory capacity (IC) 1.27, and a 15 W/min
work increase. B: COPD subject with IF 0.35, IC 2.49, and a 20 W/
min work increase. C: Normal subject with IF 0.44, IC 2.73, and a
20 W/min work increase.
exercise was lower than the IC at rest. The pattern of VT
change in the IF ⱖ 0.23 group subjects was comparable to
normal subjects, whereas the peak VT of the IF ⱖ 0.23 group
was smaller than that of control subjects. Gas exchange analysis showed that although anaerobic threshold was not statistically different between the 2 COPD groups (P ⫽ .09),
V̇E/V̇CO2 was higher in the IF ⬍ 0.23 group than the IF ⱖ 0.23
group (37.93 ⫾ 4.69 vs 34.33 ⫾ 4.76, P ⫽ .045). In addition,
72% of COPD the IF ⬍ 0.23 group subjects and 34% of the
IF ⱖ 0.23 group subjects stopped exercise due to shortness of
breath. 2% of the IF ⬍ 0.23 group subjects and 47% of the
IF ⱖ 0.23 group subjects stopped the exercise because of leg
fatigue. The results suggested that the reason for stopping
exercise was significantly different between COPD subjects
with high or low IF (P ⬍ .05).
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INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
IN
PATIENTS WITH COPD
Although many factors contribute to exercise intolerance in COPD patients, such as impairment of pulmonary
function, cardiovascular diseases, metabolic disorders,
skeletal muscle diseases, or the combination of several
diseases, one major reason is the limitation of pulmonary
function.15 In the present study we excluded COPD patients with certain severe systemic diseases that impair
pulmonary function and reduce exercise capacity.
As a key characteristic of decreased pulmonary function
in COPD patients, expiratory flow reduction progressively
promotes air trapping and lung hyperinflation, so COPD
patients display decreased IC and increased RV and TLC.
At rest these patients can extend the expiratory duration to
fully exhale, but during exercise their only way to increase
V̇E is to increase breathing frequency, due to the limitation
of the VT increment caused by a reduced IC. Therefore,
the expiratory time is further decreased and lung hyperinflation and air trapping get worse.16 Meanwhile, increased
end-expiratory lung volume in COPD patients leads to
intrinsic PEEP, which increases the work of breathing and
causes respiratory muscle fatigue and insufficient gas exchange during exercise. The combination of these events
leads to limited exercise capacity and dyspnea.17
CPET with gas exchange analysis is a powerful technique
to evaluate cardiovascular and pulmonary function.7 CPET
can noninvasively assess heart and lung function, exercise
limitation, hypoperfusion of the lung and systemic circulation, and response to therapy, and help diagnose early pulmonary hypertension and assess surgery risk. The V̇O2 increase measured at external respiration during exercise
provides information on dynamic changes of internal metabolism. Moreover, peak V̇O2 and percent-of-predicted peak
V̇O2 collected during symptom-limited CPET are the gold
standard for evaluating exercise capacity.12 Our previous studies also demonstrated that dynamic oxygen uptake parameters during exercise are effective indices for evaluating heart
and lung function in COPD patients.18,19 We chose percentof-predicted peak V̇O2 as a potential factor to evaluate exercise capacity. As an index for lung hyperinflation, IC is better
than other PFT parameters in reflecting and predicting reduced exercise capacity and ventilation impairment in COPD
patients.20-22 However, COPD patients with similar IC might
have very different TLC, so IC/TLC is better than IC alone to
reflect the increase of end-expiratory lung volume.
Our findings show that IF was significantly correlated
with percent-of-predicted peak V̇O2 and could be employed
as an independent factor to predict reduced exercise capacity in patients with moderate to severe COPD. In addition, IF was more sensitive than IC% in predicting exercise capacity in COPD patients, according to the ROC
curve analysis. Our ROC curve analysis and Youden index
calculation indicate that IF is also more sensitive than
FEV1% in predicting exercise capacity in COPD patients.
This suggests that the change of lung hyperinflation is
more predictive of the improvement of ventilation impairment than the change of expiratory air flow in stable COPD
patients after treatment with bronchodilators. A group of
studies showed that, compared to FEV1, IC was a potential
factor in evaluating the effects of bronchodilators in COPD
patients.23-25 The sensitivity, specificity, and Youden index of IF in predicting exercise capacity in COPD subjects
were 0.861, 0.929, and 0.79 when 0.23 was selected as the
IF cutoff. This suggests that 0.23 is a proper cutoff for IF
as a predictor. Further comparison showed that the COPD
subjects with IF ⬍ 0.23 had worse lung hyperinflation,
ventilation impairment, and exercise capacity reduction,
indicating that IF is a robust predictor of COPD severity.
Our findings are consistent with those of Albuquerque
et al, who reported that an IF 0.28 was a good predictor of
exercise intolerance in COPD subjects.4 Also, Vassaux et al
found that COPD subjects with an IF ⬍ 0.25 possessed worse
percent-of-predicted peak V̇O2 and peak O2 pulse than subjects with an IF ⬎ 0.25.26 Another study found that IF was an
independent predictor of mortality risk in COPD subjects,
and that COPD subjects with an IF ⬍ 0.25 had worse pulmonary function and higher mortality risk.27 The IF cutoff we
found in our study was different from these other reports,
which might be because of a different cohort size, different
ethnicities of the subjects, and/or different COPD phenotypes.
Our CPET results showed no significant difference in peak
breathing frequency between the 2 COPD groups. However,
the peak VT and peak V̇E of COPD subjects with an IF ⬍ 0.23
were lower than those with an IF ⱖ 0.23. Seventy-two percent of the IF ⬍ 0.23 group stopped the exercise due to
shortness of breath, indicating that the limited VT increase
was not sufficient to meet their ventilation demand during
exercise, and the increased neuromuscular dissociation. We
also noticed that (see Fig. 4), due to the reduction of IC, the
increment of VT in the IF ⬍ 0.23 group was significantly
smaller than that in the IF ⱖ 0.23 group. Also, the VT in the
IF ⬍ 0.23 group was very close to their IC, indicating that
subjects in the IF ⬍ 0.23 group had more severe dynamic
hyperinflation. Therefore, an increased respiratory muscle
work in the IF ⬍ 0.23 group was required to overcome the
lung dynamic elastance caused by gradually increasing endexpiratory lung volume.28 Clearly, the only way of increasing
exercise capacity in the IF ⬍ 0.23 group was to increase the
breathing frequency earlier, and they would stop exercise
earlier because of respiratory distress. Meanwhile, a worse
ventilation-to-perfusion ratio could have caused exertional
dyspnea, thereby dramatically reducing exercise capacity. Because the V̇E and carbon dioxide production were simultaneously limited in the exercise, it was difficult to compare V̇E/
V̇CO2 at anaerobic threshold between the 2 COPD groups. In
addition, the percent-of-predicted peak O2 pulse in the
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1929
Discussion
INSPIRATORY FRACTION CORRELATES WITH EXERCISE CAPACITY
IF ⬍ 0.23 group was less than that of the IF ⱖ 0.23 group.
This might be caused by severe hyperinflation-induced reduction of left ventricular end-diastolic volume, reduced right heart
blood volume, and/or increased left ventricular after-load.26,29
Due to our small sample size, we cannot rule out that
another cutoff value of IF and other physiological variables
might be superior to IF 0.23 to evaluate exercise capacity in
patients with stable, moderate to severe COPD. The reasons
for stopping exercise were significantly different between the
2 COPD groups, whereas there was no significant difference
in peak V̇E/MVV. It is possible that our cohort size was not
big enough, or that the specificity of peak V̇E/MVV is not
significant. Therefore, it is critical to further study the effects
of dynamic hyperinflation on exercise capacity.
Conclusions
9.
10.
11.
12.
13.
14.
15.
16.
IF significantly correlates with and independently predicts exercise capacity in patients with stable, moderate to
severe COPD. Compared to the COPD subjects with
IF ⬎ 0.23, the subjects with IF ⬍ 0.23 had worse lung
hyperinflation, less exercise capacity, and more reduced
peak VT, peak V̇E, and percent-of-predicted peak O2 pulse.
Our findings support the hypothesis that IF is a useful
predictor of exercise capacity in COPD patients, and might
help physicians choose individual treatment plans.
19.
ACKNOWLEDGMENTS
20.
We thank the study participants and the technicians of our pulmonary
function laboratory.
21.
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